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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Structural basis of a novel Interferon b signaling axis mediated via the ifnar1 receptor

ABSTRACT: Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?. Interferon b induced gene expression in peritoneal exudate cells was measured 3hr post intra-peritoneal injection of 10,000IU/ml of interferon beta or saline into wildtype and Ifnar2-/- mice. Three independant experiments were performed for each treatment in both genotypes using different mice for each sample.

ORGANISM(S): Mus musculus

SUBMITTER: Sam Forster

PROVIDER: E-GEOD-48827 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Structural basis of a novel Interferon b signaling axis mediated via the ifnar1 receptor

Project description:Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?.

2013-07-13 | GSE48827 | GEO

Synthetic mimetics assigned a major role to IFNAR2 in type I Interferon signaling

Project description:Type I Interferons (IFNs) are potent inhibitors of viral replication. Here, we reformatted the natural murine and human type I Interferon-α/β receptors IFNAR1 and IFNAR2 into fully synthetic biological switches. The transmembrane and intracellular domains of natural IFNAR1 and IFNAR2 were conserved, whereas the extracellular domains were exchanged by nanobodies directed against the fluorescent proteins Green fluorescent protein (GFP) and mCherry. Using this approach, multimeric single-binding GFP-mCherry ligands induced synthetic IFNAR1/IFNAR2 receptor complexes and initiated STAT1/2 mediated signal transduction via Jak1 and Tyk2. Homodimeric GFP and mCherry ligands showed that IFNAR2 but not IFNAR1 homodimers were sufficient to induce sustained STAT1/2 signaling. Transcriptome analysis revealed that synthetic murine type I IFN signaling was highly comparable to IFNα4 signaling and resulted in efficient elimination of vesicular stomatitis virus (VSV) in a cell culture based viral infection model using MC57 cells stimulated with synthetic type IFN ligands. Using intracellular deletion variants and point mutations, Y510 and Y335 in murine IFNAR2 were verified as unique phosphorylation sites for STAT1/2 activation, whereas the other tyrosine residues in IFNAR1 and IFNAR2 were not involved in STAT1/2 phosphorylation. Comparative analysis of synthetic human IFNARs supporting this finding. In summary, our data showed that synthetic type I IFN signal transduction is originating from IFNAR2 rather than IFNAR1.

2022-09-21 | GSE202839 | GEO

ATAC-seq of MORC3 deficient BLaER1 monocytes [ATAC-seq]

Project description:We have identified MORC3 as a negative regulator of Type I Interferon (IFN), whose absence induces IFN and interferon-stimulated genes (ISGs). To study the global effects of MORC3 on DNA accessibility, we deleted MORC3 in IFNAR1-/- IFNAR2-/- BLaER1 monocytes and performed ATAC-seq.

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Transcriptional profile of MORC3 deficient BLaER1 monocytes [KO]

Project description:We have identified MORC3 as a negative regulator of Type I Interferon (IFN), whose absence induces IFN and interferon-stimulated genes (ISGs). To study the global transcriptional effects of loss of MORC3, we deleted MORC3 in WT, IFNAR1–/– IFNAR2–/– and IFNB1–/– BLaER1 monocytes and performed RNA-seq.

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Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

Project description:Type I interferon (IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to regulate sterile and infectious immunity. IFNAR1 expression is tightly regulated to prevent autoimmunity although the mechanisms governing this are incompletely understood. We investigated the strategies used by two flaviviruses, tick-borne encephalitis virus and West Nile virus, to antagonize IFN-I signaling. Infection with these viruses resulted in depletion of IFNAR1 associated with the function of the viral IFN-I antagonist, NS5. NS5 function was dependent on its ability to associate with prolidase (PEPD), a cellular dipeptidase. PEPD was required for IFNAR1 maturation and accumulation, as well as gene induction following IFNAR1 stimulation. The relevance of PEPD to human biology was confirmed in fibroblasts derived from patients with genetic prolidase deficiency that expressed low IFNAR1 and exhibited reduced responses to IFNAR1. Thus, by understanding flavivirus IFN-I antagonism, PEPD is revealed as a central regulator of IFN-I responses in humans. RNA was isolated from replicates of 4 cultured dermal fibroblast lines derived from patients with genetic prolidase deficiency (PEPD), as well as from 4 cultured dermal fibroblast lines derived from normal healthy donors. These were run on Agilent microarrays to compare differences in gene expression observed in PEPD fibroblasts compared with normal fibroblasts.

2015-07-08 | E-GEOD-64387 | biostudies-arrayexpress

Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

2015-07-08 | GSE64387 | GEO

Whole transcriptome shotgun sequencing of type 1 IFN key proteins knock out clones

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2020-08-14 | GSE118551 | GEO

Microarray analysis of IFN-response

Project description:Type I interferon (IFN-α/β) is the first line of defense against viral infection. Mouse models have been pivotal to our understanding of IFN-α/β in immunity, although validation of these findings in humans has not been possible. We investigated a previously healthy child with fatal susceptibility to the live-attenuated measles, mumps and rubella (MMR) vaccine. By targeted resequencing we identified a homozygous mutation in the high-affinity interferon-α/β receptor (IFNAR2), which rendered cells unresponsive to IFN-α/β and led to unrestricted replication of IFN-attenuated viruses. Reconstitution of patient cells with wild-type IFNAR2 restored IFN-α/β responsiveness and viral resistance. Despite the failure to control vaccine viruses, the patient showed no evidence of susceptibility to conventional viral pathogens in vivo and adaptive immunity appeared normal. Human IFNAR2 deficiency therefore reveals an essential role for IFN-α/β in resistance to attenuated viruses, but significant and unexpected redundancy overall in antiviral immunity. Total RNA isolated from IFNAR2-deficient patient (in triplicate) and control (three independent control lines) fibroblasts treated with IFNalpha, IFNbeta or IFNgamma (1000 IU/mL) for 10h

2015-06-12 | E-GEOD-67737 | biostudies-arrayexpress

Tumour cells can escape antiproliferative pressure by type I interferon through immunoediting of interferon receptor expression

Project description:Type I interferons (IFNs) play a central role in innate immunity against virus infection, but also in the antitumour response. In tumour biology, an important mechanism of action apart from the more indirect immune-modulatory and anti-angiogenic effects of IFNs, is their direct impact on cell proliferation. Particularly for cancers arising in the context of chronic inflammation, constant exposure of cells to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of tumour subclones or -populations that developed resistance to the antiproliferative effects of IFN might constitute an important contribution to immunoediting of the tumour leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

2023-11-21 | PXD043761 | Pride

BID is critical for IFN-alpha-induced cell death

Project description:Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in IFN-alpha-induced cell death have not been clearly identified. Our previous study indicated that IFN (alpha, beta and omega) receptor (IFNAR) 1/2- and IFN regulatory factor (IRF) 9-RNA interference (RNAi) completely inhibited the antiproliferative (AP) activity of IFN-alpha in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-alpha., followed by transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, IFNAR1/2- and IRF9-RNAi inhibited the gene expression of TRAIL, but not of Fas ligand (FasL), following IFN-alpha treatment. In fact, TRAIL but not FasL inhibited the proliferation of OVCAR3 cells. IFN-alpha notably up-regulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. Following TRAIL signaling, Caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly abrogated both AP activities of IFN-alpha and TRAIL. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi m). Finally, we provide important new evidence that BID overexpression led to a major enhancement of both AP activities of IFN-alpha and TRAIL in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial in IFN-alpha-induced cell death, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors. Biological replicate samples were created by treating OVCAR3 cells with IFN-alpha2c (n=8); IFNAR1-RNAi and IFN-alpha2c (n=4); IFNAR2-RNAi and IFN-alpha2c (n=5); ISGF3gamma-RNAi and IFN-alpha2c (n=3); and Negative RNAi and IFN-alpha2c (n=3). For analysis, the eight IFN-alpha2c treated OVCAR3 samples were paired with an untreated OVCAR3 control sample. The 15 RNAi treated OVCAR3 samples were paired with a Negative RNAi control sample.

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